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【结 构 式】 
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【分子编号】35366 【品名】2-(2-pyridinyl)acetic acid 【CA登记号】16179-97-8 |
【 分 子 式 】C7H7NO2 【 分 子 量 】137.13812 【元素组成】C 61.31% H 5.14% N 10.21% O 23.33% |
合成路线1
该中间体在本合成路线中的序号：(X)The acetylation of clarithromycin (I) with acetic anhydride gives the diacetate (II), which is acylated with CDI yielding the 12-O-(imidazolylcarbonyl compound (III). The cyclization of (III) with ethylenediamine (IV) affords the cyclic carbamate (V), which is alkylated by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 to give the secondary amine (VII). The methylation of this amine with formaldehyde and NaBH(OAc)3 yields the corresponding tertiary amine (VIII), which is treated with aqueous HCl to provide the descladinosyl compound (IX). Finally, this compound is acylated with 2-(2-pyridyl)acetic acid (X) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), and deacetylated with methanol to afford the target compound.
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 【2】 Ishii, T.; Tanikawa, T.; Matsuura, A.; Sugimoto, T.; Asaka, T.; Kashimura, M. (Taisho Pharmaceutical Co., Ltd.); Erythromycin A derivs.. EP 0945459; WO 9823628 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (II) | 35359 | C43H75NO14 | 详情 | 详情 | ||
| (III) | 35360 | C47H75N3O14 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (V) | 35361 | C46H79N3O14 | 详情 | 详情 | ||
| (VI) | 35374 | 5,6-dihydro-3-pyridinecarbaldehyde | C6H7NO | 详情 | 详情 | |
| (VII) | 35375 | C52H84N4O14 | 详情 | 详情 | ||
| (VIII) | 35376 | C53H86N4O14 | 详情 | 详情 | ||
| (IX) | 35377 | C43H70N4O10 | 详情 | 详情 | ||
| (X) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The selective hydrolysis of clarithromycin (I) with aqueous HCl, followed by acylation with acetic anhydride gives the monoacetylated descladinosyl compound (XI), which by reaction with trichloromethyl chloroformate (TCF) yields the cyclic carbonate (XII). The reaction of (XII) with 1,1,3,3-tetramethylguanidine (TMG) affords intermediate (XIII), which is selecti-ely acylated with 2-(2-pyridyl)acetic acid (X) and WSC giving the 3-O-acylated compound (XIV). The activation of (XIV) with CDI affords the 12-O-imidazolylcarbonyl derivative (XV), which is cyclized with ethylenediamine (IV) providing the carbamate (XVI). The alkylation of the primary amine of (XVI) by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 gives the secondary amine (XVII).
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VI) | 35374 | 5,6-dihydro-3-pyridinecarbaldehyde | C6H7NO | 详情 | 详情 | |
| (X) | 35369 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,13S,14R)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-6-yl]oxy]-4-methylcyclohexyl acetate | C33H57NO9 | 详情 | 详情 | |
| (XI) | 35367 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-methylcyclohexyl acetate | C33H59NO10 | 详情 | 详情 | |
| (XII) | 35368 | (1R,2R,4R,6S)-2-[[(3aR,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxododecahydro-4H-[1,3]dioxolo[4,5-c]oxacyclotetradecin-10-yl]oxy]-6-(dimethylamino)-4-methylcyclohexyl acetate | C34H57NO11 | 详情 | 详情 | |
| (XIII) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
| (XIV) | 35370 | (3R,4S,5R,6R,7R,9R,13S,14R)-6-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-4-yl 2-(2-pyridinyl)acetate | C40H62N2O10 | 详情 | 详情 | |
| (XV) | 35371 | (2R,3S,7R,9R,10R,11R,12S,13R)-10-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-[[2-(2-pyridinyl)acetyl]oxy]oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C44H64N4O11 | 详情 | 详情 | |
| (XVI) | 35372 | C43H68N4O11 | 详情 | 详情 | ||
| (XVII) | 35378 | C49H73N5O11 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The acetylation of clarithromycin (I) with acetic anhydride gives the diacetate (II), which is acylated with CDI yielding the 12-O-(imidazolylcarbonyl) compound (III). The cyclization of (III) with ethylenediamine (IV) affords the cyclic carbamate (V), which is alkylated by reductocondensation with quinoline-3-carbaldehyde (VI) and NaBH(OAc)3 to give the secondary amine (VII). The methylation of this amine with formaldehyde and NaBH(OAc)3 yields the corresponding tertiary amine (VIII), which is treated with aqueous HCl to provide the descladinosyl compound (IX). Finally, this compound is acylated with 2-(2-pyridyl)acetic acid (X) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and deacetylated with methanol to afford the target compound.
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 【2】 Ishii, T.; Tanikawa, T.; Matsuura, A.; Sugimoto, T.; Asaka, T.; Kashimura, M. (Taisho Pharmaceutical Co., Ltd.); Erythromycin A derivs.. EP 0945459; WO 9823628 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (II) | 35359 | C43H75NO14 | 详情 | 详情 | ||
| (III) | 35360 | C47H75N3O14 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (V) | 35361 | C46H79N3O14 | 详情 | 详情 | ||
| (VI) | 35362 | 3-quinolinecarbaldehyde | 13669-42-6 | C10H7NO | 详情 | 详情 |
| (VII) | 35363 | C56H86N4O14 | 详情 | 详情 | ||
| (VIII) | 35364 | C57H88N4O14 | 详情 | 详情 | ||
| (IX) | 35365 | (1R,2R,4R,6S)-2-[((3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-[2-[methyl(3-quinolinylmethyl)amino]ethyl]-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-6-(dimethyl | C47H72N4O10 | 详情 | 详情 | |
| (X) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The selective hydrolysis of clarithromycin (I) with aqueous HCl, followed by acylation with acetic anhydride gives the monoacetylated descladinosyl compound (XI), which by reaction with trichloromethyl chloroformate (TCF) yields the cyclic carbonate (XII). The reaction of (XII) with 1,1,3,3-tetramethylguanidine (TMG) affords intermediate (XIII), which is selectively acylated with 2-(2-pyridyl)acetic acid (X) and WSC giving the 3-O-acylated compound (XIV). The activation of (XIV) with CDI affords the 12-O-imidazolylcarbonyl derivative (XV), which is cyclized with ethylenediamine (IV) providing the carbamate (XVI). The alkylation of the primary amine of (XVI) by reductocondensation with quinoline-3-carbaldehyde (VI) and NaBH(OAc)3 gives the secondary amine (XVII).
| 【1】 Tanikawa, T.; Akashi, T.; Manaka, A.; Suzuki, K.; Asaka, T.; Adachi, T.; Ishii, T.; Sugiyama, H.; Kashimura, M.; Saito, H.; Morimoto, S.; Structure activity studies leading potent acyclides: 3-O-Acyl-5-O-desosaminylerythronolide 11,12-carbamates. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2159. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 35358 | C39H71NO12 | 详情 | 详情 | ||
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VI) | 35362 | 3-quinolinecarbaldehyde | 13669-42-6 | C10H7NO | 详情 | 详情 |
| (X) | 35369 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,13S,14R)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-6-yl]oxy]-4-methylcyclohexyl acetate | C33H57NO9 | 详情 | 详情 | |
| (XI) | 35367 | (1R,2S,4R,6R)-2-(dimethylamino)-6-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-methylcyclohexyl acetate | C33H59NO10 | 详情 | 详情 | |
| (XII) | 35368 | (1R,2R,4R,6S)-2-[[(3aR,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxododecahydro-4H-[1,3]dioxolo[4,5-c]oxacyclotetradecin-10-yl]oxy]-6-(dimethylamino)-4-methylcyclohexyl acetate | C34H57NO11 | 详情 | 详情 | |
| (XIII) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
| (XIV) | 35370 | (3R,4S,5R,6R,7R,9R,13S,14R)-6-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-4-yl 2-(2-pyridinyl)acetate | C40H62N2O10 | 详情 | 详情 | |
| (XV) | 35371 | (2R,3S,7R,9R,10R,11R,12S,13R)-10-[[(1R,2R,3S,5R)-2-(acetoxy)-3-(dimethylamino)-5-methylcyclohexyl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-[[2-(2-pyridinyl)acetyl]oxy]oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C44H64N4O11 | 详情 | 详情 | |
| (XVI) | 35372 | C43H68N4O11 | 详情 | 详情 | ||
| (XVII) | 35373 | C53H75N5O11 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)4-Formylbenzonitrile (I) was converted to oxime (II) by treatment with hydroxylamine hydrochloride in pyridine-ethanol. Chlorination of the oxime with NaOCl, followed by dehydrohalogenation of the intermediate imidoyl chloride and dipolar cycloaddition to vinylacetic acid (III) produced the racemic isoxazoline (IV). The cyano group of (IV) was then converted to amidine (V) by formation of the corresponding imidate and subsequent treatment with methanolic ammonia. After protection of the amidine function of (V) as the Boc-derivative, ester hydrolysis employing LiOH yielded carboxylic acid (VI). Methyl 2-piperidine acetate (VIII) was obtained by catalytic hydrogenation of 2-pyridylacetic acid (VII) in the presence of MeOH and HCl. Coupling of acid (VI) with the racemic methyl 2-piperidineacetate (VIII) in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoborate (TBTU) furnished a diastereomeric mixture of amides (IX). Cleavage of the Boc group of (IX) by means of either trifluoroacetic acid or methanolic HCl provided amidine (X). Finally, basic hydolysis of the methyl ester of (X) gave rise to the title compound.
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 【2】 Olson, R.E.; Wityak, J.; Wexler, R.R.; Sielecki, T.M.; Mous, S.A.; Liu, J.; Thoolen, M.; Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2000, 10, 5, 449. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (II) | 17553 | 4-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (III) | 33753 | 3-butenoic acid | 625-38-7 | C4H6O2 | 详情 | 详情 |
| (IV) | 40752 | 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (V) | 28137 | methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C13H15N3O3 | 详情 | 详情 | |
| (VI) | 28139 | 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C17H21N3O5 | 详情 | 详情 | |
| (VII) | 35366 | 2-(2-pyridinyl)acetic acid | 16179-97-8 | C7H7NO2 | 详情 | 详情 |
| (VIII) | 40753 | methyl 2-(2-piperidinyl)acetate | C8H15NO2 | 详情 | 详情 | |
| (IX) | 40750 | methyl 2-(1-[2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetyl]-2-piperidinyl)acetate | C25H34N4O6 | 详情 | 详情 | |
| (X) | 40751 | methyl 2-[1-[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]-2-piperidinyl]acetate | C20H26N4O4 | 详情 | 详情 |